Sepsis is most commonly induced by a systemic infection of Gram negative bacteria and today, when infections caused by antibiotic resistant strains of bacteria constitute a major problem, alternative methods for prevention and treatment are required. Earlier studies, in vitro and in vivo, have revealed that compositions containing immobilized heparin have prophylactic properties on microbial infections. Also, an inflammatory response caused by bioincompatibility of extracorporeal circuits is a major clinical issue and can ultimately lead to sepsis.
Heparan sulfates are proteoglycans that are present on the surface of almost all mammalian cells. Many microorganisms utilize heparan sulfates on the surface of the mammalian cell as receptors. Furthermore, inflammatory cells and cytokines utilize heparan sulfates on the cell surface for binding and activation. Heparin is another proteoglycan with a molecular weight of 15-25 kDa that is isolated from proteoglycans in basophilic granules of mast cells in mammalian tissue. Due to the structural similarity between heparin and heparan sulfates, heparin immobilized on a solid surface binds bacteria, virus and parasites as well as inflammatory cells and cytokines.
The development of a pro-inflammatory state is associated with a dramatically increased morbidity and mortality in a number of mammalian diseases, including septicemia, viraemia, acute or chronic renal disease, cardiovascular disease, hypovolemic shock, anaphylactic reactions and autoimmune disease. Tissue damage and organ dysfunction may be caused not only by alien microorganisms, but also by pro-inflammatory mediators released in response to such an infection or due to surface activation by conventional extracorporeal circuits (complement activation, etc.). Cytokines (such as tumor necrosis factor, interleukin-1, interleukin-6) and non-cytokines (such as nitric oxide, platelet-activating factor, complements, and eicosonoids) may inflict collateral tissue injury and contribute to the dysfunction of multiple organ systems as well as to organism cell death. Components from bacteria, parasites, fungi, or viruses may evoke the activation of pro-inflammatory cytokines through a plethora of cell-types. Inflammatory cells, including macrophages, lymphocytes, and granulocytes, are activated. Endogenous anti-inflammatory mediators are released in response to the infection and act to control the overwhelming systemic inflammatory response. First, the removal of pathogenic microorganisms is pivotal to diminish the inflammatory response. Second, the fragile balance between negative and positive feedback on the inflammatory mediators is the key factor that modulates the cellular damage and influences the clinical outcome, thus making the reduction of circulating pro-inflammatory stimulii and/or pro-inflammatory cytokines a key event in controlling septic complications.
U.S. Pat. No. 6,197,568 discloses methods for isolation, diagnosis and treatment of microorganisms such as flaviviruses and other hemorrhagic viruses based on the interaction of said microorganisms with heparin immobilized on agarose. Heparin-agarose as used in U.S. Pat. No. 6,197,568 comprises cleaved heparin molecules immobilized on agarose.
In Artificial Organs, 26(12):1020-1025 (2002) inflammatory cytokines are adsorbed using a heparin coated extracorporeal circuit. The extracorporeal circuit was provided with a Baxter Duraflo II heparin surface with electrostatically bound multi point attached heparin.
There is a demand for improved methods and devices for extracorporeal treatment of blood.